Pulmonary fibrosis is a disease in which fibrosis occurs in the stroma of the lung triggered by injury and collapse of pulmonary alveoli. In many cases, the cause is unknown. When the cause cannot be found, the pulmonary fibrosis is particularly termed idiopathic pulmonary fibrosis (IPF). As fibrosis progresses, the lungs harden and the oxygen exchange capacity decreases. At present, there is no definitive treatment method, and its treatment method is almost symptomatic therapy.
TGF-β is known as a cytokine that regulates cell proliferation and differentiation and is considered to also play an important role in liver or lung fibrillization. Thus, it is attracting attention as a treatment target of pulmonary fibrosis.
Nucleic acid medicine is expected as a next-generation drug discovery technology because it has both easy manufacturability of low molecular pharmaceutical products, and effectiveness and safety of antibody drugs. However, the development of the pharmaceutical products is not progressing as expected due to the barriers of instability of nucleic acid molecules in the body, side effects due to enhanced innate immune response, absence of development of efficient drug delivery system (DDS) and the like.
In the case of respiratory diseases, pulmonary fibrosis is an effective target disease of nucleic acid medicine, since topical administration of drugs to the lung is possible. To deal with the problems of nucleic acid molecule such as stability in the body and induction of innate immune response, a single-stranded nucleic acid molecule in which the terminals of a double-stranded nucleic acid of siRNA or miRNA are linked by various linkers has been developed (e.g., patent documents 1-5). Hamasaki et al. reported that symptoms were remarkably improved by intratracheal administration of a single-stranded nucleic acid molecule having the following structure carrying a TGF-β1 expression-inhibitory sequence (hereinafter to be also referred to as “PK-0051”) to model mice of pulmonary fibrosis and acute lung injury (non-patent document 1).
(SEQ ID NO: 1)5′-AGCAGAGUACACACAGCAUAUACC (SEQ ID NO: 2)-P-GGUAUAUGCUGUGUGUACUCUGCUUC-P-G-3′(Underline shows a TGF-β1 expression inhibitory sequence. P is a proline derivative linker represented by the following formula (I)).
